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Cellular reprogramming of diabetic foot ulcer fibroblasts triggers pro‐healing miRNA‐mediated epigenetic signature
Author(s) -
Pastar Irena,
Marjanovic Jelena,
Liang Liang,
Stone Rivka C.,
Kashpur Olga,
Jozic Ivan,
Head Cheyanne R.,
Smith Avi,
GeramiNaini Behzad,
Garlick Jonathan A.,
TomicCanic Marjana
Publication year - 2021
Publication title -
experimental dermatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.108
H-Index - 96
eISSN - 1600-0625
pISSN - 0906-6705
DOI - 10.1111/exd.14405
Subject(s) - reprogramming , induced pluripotent stem cell , fibroblast , downregulation and upregulation , epigenetics , microbiology and biotechnology , wound healing , microrna , biology , extracellular matrix , diabetic foot , cancer research , embryonic stem cell , cell , immunology , diabetes mellitus , cell culture , endocrinology , genetics , gene
Diabetic foot ulcers (DFUs), a prevalent complication of diabetes, constitute a major medical challenge with a critical need for development of cell‐based therapies. We previously generated induced pluripotent stem cells (iPSCs) from dermal fibroblasts derived from the DFU patients, location‐matched skin of diabetic patients and normal healthy donors and re‐differentiated them into fibroblasts. To assess the epigenetic microRNA (miR) regulated changes triggered by cellular reprogramming, we performed miRs expression profiling. We found let‐7c, miR‐26b‐5p, −29c‐3p, −148a‐3p, −196a‐5p, −199b‐5p and −374a‐5p suppressed in iPSC‐derived fibroblasts in vitro and in 3D dermis‐like self‐assembly tissue, whereas their corresponding targets involved in cellular migration were upregulated. Moreover, targets involved in organization of extracellular matrix were induced after fibroblast reprogramming. PLAT gene, the crucial fibrinolysis factor, was upregulated in iPSC‐derived fibroblasts and was confirmed as a direct target of miR‐196a‐5p. miR‐197‐3p and miR‐331‐3p were found upregulated specifically in iPSC‐derived diabetic fibroblasts, while their targets CAV1 and CDKN3 were suppressed. CAV1, an important negative regulator of wound healing, was confirmed as a direct miR‐197‐3p target. Together, our findings demonstrate that iPSC reprogramming is an effective approach for erasing the diabetic non‐healing miR‐mediated epigenetic signature and promoting a pro‐healing cellular phenotype.